Cannabis drug interactions

Case scenario 

Ping, 45, is a regular patient of the pharmacy and presents a repeat script for nortriptyline. He has had a partial response to this medicine, reporting improvements in chronic pain. When you inquire about any potential new medicines, he mentions he recently visited a new GP who prescribed a trial of a THC-dominant medicinal cannabis flower dried for vaporization, which he is yet to have dispensed. The new GP was not aware of his nortriptyline use.

Already read the CPD in the journal? Scroll to the bottom to SUBMIT ANSWERS.

Introduction 

The leaf and flower of cannabis (Cannabis sativa L; marijuana) are used for recreational and therapeutic purposes. Cannabis and cannabis-based products (CBPs) are increasingly being self-selected or prescribed in Australia for a range of conditions, including chronic pain, cancer-related pain, neuropathic pain, anxiety, depression, insomnia, autism spectrum disorder, attention deficit disorder, epilepsy and multiple sclerosis.^1,2

Pharmacists play a central role in ensuring the quality and safe use of medicines. They must ensure patients are well informed about the potential benefits and risks when prescribed CBPs and identify potential drug interactions with cannabis or CBPs, which in this article will be collectively referred to as drug-CBP interactions. 

Given the common indications for CBPs, they are often used concomitantly with other neurological, psychotropic or analgesic medicines. This article focuses on examples of clinically observed drug-CBP interactions with medicines in these classes.

Cannabis and CBP use in Australia

In 2019, cannabis was reported to be the most used illicit substance in Australia (11.6% of adults surveyed), with 23.1% reporting they sometimes or always used cannabis for medical purposes.³

Most medically prescribed CBPs in Australia are unapproved Schedule 4 or Schedule 8 therapeutic goods that can be accessed via the Special Access Scheme (SAS) or Authorised Prescriber Scheme.¹ Currently, there are only two Therapeutic Goods Administration (TGA) registered CBPs in Australia – Sativex (nabiximols) for the clinical management of multiple sclerosis spasticity, and Epidyolex (cannabidiol) for the treatment of resistant seizures associated with either Dravet syndrome or Lennox-Gastaut syndrome. Certain CBPs with high (≥98%) cannabidiol (CBD) and negligible tetrahydrocannabinol (THC) content were down-scheduled from Schedule 4 to Schedule 3 in February 2021; however, a product that meets the Schedule 3 criteria is yet to be registered in Australia.

A diverse range of cannabis and CBP formulations are available for use. Oral liquid, followed by dried herb and oil forms are the most commonly prescribed CBP formulations in Australia.¹ Recreational use of cannabis primarily involves smoking via cigarettes (joints) or water pipe, with or without tobacco.³ A range of CBPs from other countries are available to purchase online, and while it is usually allowable for a person to import some unapproved medicines into Australia for their personal use under the personal importation scheme, CBPs are excluded.⁴ They can, however, be imported following applicable procedures by specified medical practitioners on a patient’s behalf.⁴ 

Given the wide range of CBP formulations, indications and uses in Australia, pharmacists are well positioned to play a role in providing evidence-based safety advice in this area.

Mechanisms of action for interactions

The cannabis plant contains a variety of compounds that exert different pharmacological effects, and there is the potential for pharmacokinetic and pharmacodynamic interactions with medicines, dietary supplements and foods. The two main compounds (i.e. phytocannabinoids) from the cannabis plant used in CBPs are tetrahydrocannabinol (THC) and cannabidiol (CBD). 

THC, CBD and their metabolites are predominantly metabolised by phase I CYP enzymes and then phase II conjugation.⁵ These compounds can act as substrates, inhibitors and/or inducers of liver enzymes,^5-10 with resultant pharmacokinetic drug interactions.^11,12 Potential pharmacodynamic drug interactions are mostly with medicines with similar pharmacological actions.¹³

There is also the potential for pharmacokinetic and pharmacodynamic interactions between THC and CBD, their metabolites, and other potentially active ingredients such as cannabinol.¹⁴ For instance, CBD has been reported to reduce the undesirable psychotropic and tachycardic effects of THC.¹⁵ Consequently, interactions with CBPs usually refer to  the whole product rather than the individual constituents.⁵

The pharmacological effects of THC and CBD, their metabolism, and potential mechanisms for both pharmacokinetic  and pharmacodynamic drug-CBP interactions are summarised in Table 1. 

Due to the paucity of human interaction studies, relevant preclinical research is also reported.

Clinical significance of interactions 

The pharmacological effects of THC and CBD, their metabolism, and potential mechanisms for both pharmacokinetic and pharmacodynamic drug-CBP interactions are summarised in Table 1. Due to the paucity of human interaction studies, relevant preclinical research is also reported.

For this article, drug-CBP interactions involving humans and reported in controlled clinical studies were considered higher quality evidence followed by observational studies, case series and well-documented published case reports.

Table 1 – Summary of tetrahydrocannabinol and cannabidiol

 References: Kocis PT5⁵, Nasrin S⁶, Nasrin S⁷, Bansal S⁸, Bansal S⁸, Doohan PT¹⁰, Russo E¹⁵, Amaral Silva D¹⁶, Mlost J¹⁷, Atalay S¹⁸, Lim K¹⁹, Welch SP²⁰, Stout SM21²¹, Ujvary I²²

The pharmacist’s role

Given the relatively recent legislation and commencement of using medicinal CBPs in Australia, and around the world, established clinical guidance in this area continues to develop.

Pharmacists must access the most current and accurate clinical resources and information when reviewing a patient’s medicine profile and when considering the risk of interactions in this area.

Pharmacists must consider the patient they are reviewing in their entirety and use their own clinical judgement to determine the appropriate actions for each patient, in each situation.

If the concurrent use of the CBPs with medicines is deemed necessary, and there is a possibility of an interaction, the likelihood and severity of the interaction should be established, and the patient informed of any possible side effects or risks. The pharmacist should contact the prescriber to discuss these as part of routine clinical responsibilities, following all relevant professional standards and obligations.

Examples of interactions with cannabis and CBPs

Therapeutic CBPs are primarily used in the management of certain mental health, neurological and pain conditions, where polypharmacy is common, when standard or existing TGA-approved treatments have not demonstrated effectiveness. 1,67

Medicines used in the treatment of such conditions are defined by the Australian Medicines Handbook (AMH) as being neurological, psychotropic or analgesic according to the context of their use.²⁴

The following are examples of actual or potential interactions with cannabis and/or CBPs reported in humans in these therapeutic areas. 

Neurological

Due to the known effects of CBD on the central nervous system, CBPs are increasingly being used in the management of neurological conditions, including epilepsy and multiple sclerosis. The potential for interactions with some common neurological drugs has been described.¹⁴ One of the more thoroughly investigated pharmacokinetic interactions is between CBD and clobazam.^24-33 This interaction is bidirectional, resulting in an increase of both of their active metabolites (7-OH-CBD and norclobazam).^30,32

Elevated plasma concentrations are attributed to CBD inhibition of CYP2C19, and norclobazam inhibition of glucuronidation and possibly other minor CYP enzymes.²⁹ Adverse events associated with co-administration of clobazam and CBD in patients with refractory epilepsy include an increased risk of somnolence, rash, pneumonia and aggression, often requiring dose adjustments or discontinuation.²⁶

Concomitant use of CBD and valproate, with or without clobazam, and to a lesser extent clobazam only, has also been found to increase the risk of drug-induced liver injury compared to each of the drugs alone. The risk was highest for patients administered higher CBD doses (20 mg/kg/day).^34,35

An example of an identified pharmacodynamic interaction is between THC and baclofen. It was found that the effects of both drugs were significantly enhanced, leading to an increase in heart rate and reduced cognitive and psychomotor performance.³⁶ As baclofen is a GABAB agonist, the investigators propose the potential role of THC acting on GABAB receptors in the brain.³⁶ An interaction between lithium and CBD was implicated in a case of lithium toxicity; the authors attributed this to a combination of reduced fluid intake and possibly CBD-induced renal dysfunction causing a reduction in lithium excretion.³⁷ Concomitant medicines included clonidine, felbamate and clobazam. Despite halving the clobazam dose during the introduction and upwards titration of CBD, the patient deteriorated until lithium was discontinued.³⁷ The case highlights the complexity of managing interactions with concomitant polypharmacy.

Psychotropic 

Psychotropic medicines are used in the management of various disorders such as depression, anxiety, psychosis and substance addiction. 

Several case reports have reported serious clinical interactions between cannabis and the tricyclic antidepressants amitriptyline, nortriptyline and desipramine, leading to hospitalisations. ^38-40 The combined effects of the beta-adrenergic activity from THC⁴¹ and the anticholinergic activity from tricyclic antidepressants was hypothesised to be the trigger of acute tachycardia. It is unclear if CYP enzymes are implicated, as symptoms occurred within 30 minutes and in all cases the symptoms appeared shortly after smoking marijuana, suggesting a pharmacodynamic effect.³⁹ Delirium was another common feature that the authors noted was unexpected with the relatively low doses of THC.³⁸

Consequently, pharmacokinetic interactions (or drug contamination despite drug urine testing) could not be completely excluded.³⁸ This highlights the need for research to investigate the underlying mechanisms and whether cannabis interacts with other anticholinergic medicines. 

The risk of interactions with other antidepressant drugs is uncertain. A small case series (n = 6) observed a statistically significant increase in plasma citalopram levels following initiation of CBD due to inhibition of CYP3A4 and CYP2C19; however, the clinical significance is unclear.42 Based on one case report, there may also be a risk of interaction between CBD and fluoxetine for patients with CYP2D6*4 genotype.⁴³

THC is known to generate psychotomimetic effects through mechanisms yet to be fully elucidated.⁴⁴ The use of antipsychotics including haloperidol and olanzapine have been shown to reduce THC-induced positive symptoms of psychosis in healthy adults.^45,46 This was attributed to their antagonistic actions on neurotransmitters such as dopamine, serotonin and histamine receptors.^45,46

Psychostimulants including dexamphetamine and methylphenidate have been observed to produce additive cardiovascular effects when combined with cannabis or CBPs.^47,48 Observed effects on patients included an increased heart rate and blood pressure that might reflect a synergistic pharmacodynamic interaction with THC.⁴¹

Analgesic 

CBPs are increasingly being used for the management of chronic musculoskeletal, neuropathic and cancer-related pain. Beneficial and detrimental effects from interactions with analgesic medicines are reported. For example, a synergistic  interaction between THC and opioids such as morphine and oxycodone may improve pain relief.^49-53 THC has been shown to activate κ and δ opioid receptors and enhance dopamine release from the nucleus accumbens in a similar manner to opioids, in turn improving patient-reported analgesia compared to the opioid alone.^49-53

However, such synergistic effects are not without some risks. CBD may inhibit UGT2B7, which is an enzyme involved in the metabolism of various opioids including morphine.³⁵ Madden et al reported potential methadone toxicity when used in conjunction with CBD.⁵⁴ Inhibition of CYP3A4 and CYP2C19 reduces methadone metabolism and thus increases methadone plasma concentration and the likelihood of drowsiness and fatigue.⁵⁴ Inhibition of CYP3A4 by cannabis resulted in increased plasma concentration of buprenorphine, giving rise to the possibility of buprenorphine toxicity.⁵⁵

Given these synergetic and pharmacokinetic interactions, it is essential that patients concurrently using cannabis or CBPs with opioids are closely monitored by healthcare professionals.

Further examples 

Table 2 compiles further examples of analgesic, psychotropic and neurological medicines that have been found to interact with cannabis or CBPs. When considering this information, please refer to the detail in the sections ‘The pharmacist’s role’ and ‘Clinical significance of interactions’.

Table 2 – Further examples of clinically observed cannabis or drug-CBP interactions with analgesic, psychotropic and neurological medicines.

Knowledge to practice

Health professionals involved in the prescribing and supply of CBPs should

be familiar with potential drug-CBP interactions. Pharmacists should routinely inquire about a patient’s medicine use to determine if the supply or current use of cannabis or CBPs poses a risk of drug interaction. The pharmacist must review the patient’s medicine list for any likely or potential interactions and discuss these with the patient and their prescriber prior to supply. As clinical guidance and information in this area continues to develop and emerge, pharmacists need to ensure they are accessing the most current information and clinical resources when reviewing a patient’s medicine profile and making recommendations on potential drug interactions with cannabis or CBPs. 

Pharmacists can educate health professionals who prescribe CBPs, and the patients who use them, on known and potential drug interactions and reduce the risk of avoidable adverse effects.

Conclusion 

Pharmacists can play a vital role in recognising and preventing drug-CBP interactions in people taking concomitant medicines. Considering the many CBP formulations, indications and uses, and the variables involved, pharmacists are in an ideal position to provide evidence-based safety advice in this area. Pharmacists should commit to ongoing learning and education as clinical evidence emerges. 

Key Points 

• ​​Cannabis and CBPs have the potential to interact with many medicines due to their involvement in several physiological pathways in the brain, CYP and UGT enzymes, and due to pharmacodynamic effects.
• Examples of medicines for which there is clinical evidence of drug interactions with cannabis and/or CBPs include baclofen, lithium, clobazam, tricyclic antidepressants and opioids.
• Given that available clinical information in this area continues to develop, pharmacists should refer to the most current information and clinical resources when reviewing a patient’s medicine profile for potential interactions with cannabis or CBPs. 

If you do get an enrolment error, please click here

References

1. Medicinal cannabis Special Access Scheme Category B data Canberra, ACT: Australian
Government, Department of Health and Aged Care, Therapeutic Goods Administration.
At: www.tga.gov.au/products/unapproved-therapeutic-
goods/medicinal-cannabis-hub/medicinal-cannabis-access-pathways-and-patient-access-
data
2. de Carvalho Reis R, Almeida KJ, da Silva Lopes L, et al. Efficacy and adverse event profile of cannabidiol and medicinal cannabis for treatment-
resistant epilepsy: systematic review and meta-analysis. Epilepsy & Behavior
2020;102:106635.
3. Australian Institute of Health and Welfare. Alcohol, tobacco & other drugs in Australia.
AIHW, 2022. At:
www.aihw.gov.au/reports/alcohol/alcohol-tobacco-other-drugs-australia/contents/drug-
types/cannabis
4. Medicinal cannabis: importation and the traveller's exemption Canberra, ACT: Australian
Government, Department of Health and Aged Care, Therapeutic Goods Administration.
At: www.tga.gov.au/medicinal-cannabis-importation-and-travellers-
exemption
5. Kocis PT, Vrana KE. Delta-9-Tetrahydrocannabinol and cannabidiol drug-drug
interactions. Medical Cannabis and Cannabinoids 2020;3(1):61–73.
6. Nasrin S, Watson CJW, Perez-Paramo YX, et al. Cannabinoid metabolites as
inhibitors of major hepatic CYP450 enzymes, with implications for cannabis-drug
interactions. Drug Metabolism & Disposition 2021;49(12):1070–80.
7. Nasrin S, Watson CJ, Chen G, et al. Cannabinoid metabolites as potential inhibitors
of major CYP450 enzymes. Implication for cannabis-drug interactions. FASEB Journal
Conference: Experimental Biology Meeting, EB. 2020;34(SUPPL 1).
8. Bansal S, Maharao N, Paine MF, et al. Predicting the Potential for Cannabinoids
to Precipitate Pharmacokinetic Drug Interactions via Reversible Inhibition or Inactivation
of Major Cytochromes P450. Drug Metabolism & Disposition. 2020;48(10):1008-17.
9. Bansal S, Paine MF, Unadkat JD. Comprehensive Predictions of Cytochrome P450
(P450)-Mediated In Vivo Cannabinoid-Drug Interactions Based on Reversible and Time-
Dependent P450 Inhibition in Human Liver Microsomes. Drug Metabolism and
Disposition. 2022;50(4):351-60.
10. Doohan PT, Oldfield LD, Arnold JC, Anderson LL. Cannabinoid Interactions with
Cytochrome P450 Drug Metabolism: a Full-Spectrum Characterization. AAPS Journal.
2021;23(4) (no pagination)(91).
11. Antoniou T, Bodkin J, Ho JMW. Drug interactions with cannabinoids. Cmaj.
2020;192(9):E206.
12. Qian Y, Gurley BJ, Markowitz JS. The Potential for Pharmacokinetic Interactions Between
Cannabis Products and Conventional Medications. Journal of Clinical
Psychopharmacology. 2019;39(5):462-71.
13. Cohen K, Weizman A, Weinstein A. Positive and negative effects of cannabis and
cannabinoids on health. Clinical Pharmacology & Therapeutics. 2019;105(5):1139-47.
14. Lopera V, Rodriguez A, Amariles P. Clinical Relevance of Drug Interactions with
Cannabis: A Systematic Review. Journal of Clinical Medicine. 2022;11(5) (no
pagination)(1154).
15. Russo E, Guy GWJMh. A tale of two cannabinoids: the therapeutic rationale for
combining tetrahydrocannabinol and cannabidiol. 2006;66(2):234-46.
16. Amaral Silva D, Pate DW, Clark RD, Davies NM, El-Kadi AOS, Lobenberg R.
Phytocannabinoid drug-drug interactions and their clinical implications. Pharmacology
and Therapeutics. 2020;215 (no pagination)(107621).
17. Mlost J, Bryk M, Starowicz K. Cannabidiol for Pain Treatment: Focus on Pharmacology
and Mechanism of Action. International Journal of Molecular Sciences. 2020;21(22):8870.
18. Atalay S, Jarocka-Karpowicz I, Skrzydlewska EJA. Antioxidative and anti-inflammatory
properties of cannabidiol. 2019;9(1):21.
19. Lim K, See YM, Lee JJCP, Neuroscience. A systematic review of the effectiveness of
medical cannabis for psychiatric, movement and neurodegenerative disorders.
2017;15(4):301.
20. Welch SP. Interaction of the cannabinoid and opioid systems in the modulation of
nociception. International Review of Psychiatry. 2009;21(2 SPEC. ISS.):143-51.
21. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of
human drug metabolizing enzymes: A systematic review. Drug Metabolism Reviews.
2014;46(1):86-95.
22. Ujvary I, Hanus L. Human Metabolites of Cannabidiol: A Review on Their Formation,
Biological Activity, and Relevance in Therapy. Cannabis and Cannabinoid Research.
2016;1(1):90-101.
23. Coxeter P, McLachlan AJ, Duke C, Roufogalis B. Herb-drug interactions: an evidence
based approach. Current medicinal chemistry. 2004;11(11):1513-25.
24. Rossi S, ed. Australian medicines handbook online. Adelaide: Australian Medicines
Handbook; 2022. At: https://amhonline.amh.net.au/
25. Critchley D, Szaflarski J, Patsalos P, Gidal B, VanLandingham K, Morrison G. Drug-drug
Interaction Studies with Coadministration of Cannabidiol (CBD) and Clobazam, Valproate,
Stiripentol or Midazolam in Healthy Volunteers and Adults with Epilepsy. Epilepsy and
Behavior. 2019;Part B. Conference: 7th London-Innsbruck Colloquium on Status
Epilepticus and Acute Seizures. Francis Crick Institute(106735).
26. Devinsky O, Thiele EA, Wright S, Checketts D, Morrison G, Dunayevich E, et al.
Cannabidiol efficacy independent of clobazam: Meta-analysis of four randomized
controlled trials. Acta Neurologica Scandinavica. 2020;142(6):531-40.
27. Gaston T, Bebin E, Szaflarski J. Importance of monitoring clobazam and N-desmethylclobazam levels in treatment with cannabidiol (CBD) for epilepsy. Neurology
Conference: 68th American Academy of Neurology Annual Meeting, AAN. 2016;86(16
SUPPL. 1).
28. Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam
and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56(8):1246-51.
29. Klein P, Tolbert D, Gidal BE. Drug-drug interactions and pharmacodynamics of
concomitant clobazam and cannabidiol or stiripentol in refractory seizures. Epilepsy and
Behavior. 2019;99 (no pagination)(106459).
30. Morrison G, Crockett J, Blakey G, Sommerville K. A Phase 1, Open-Label,
Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam,
Stiripentol, or Valproate and Cannabidiol in Healthy Subjects. Clinical Pharmacology in
Drug Development. 2019;8(8):1009-31.
31. Savage TE, Sourbron J, Bruno PL, Skirvin LA, Wolper ES, Anagnos CJ, et al. Efficacy of
cannabidiol in subjects with refractory epilepsy relative to concomitant use of clobazam.
Epilepsy Research. 2020;160 (no pagination)(106263).
32. Szaflarski J, Patsalos P, Gidal B, Van Landingham K, Critchley D, Morrison G. Drug-drug
interaction (DDI) studies with coadministration of cannabidiol (CBD) and clobazam (CLB),
valproate (VPA), stiripentol (STP) or midazolam (MDZ) in healthy volunteers (HVTs) and
adults with epilepsy. Neurology Conference: 71st Annual Meeting of the American
Academy of Neurology, AAN. 2019;92(15 Supplement 1).
33. VanLandingham KE, Crockett J, Taylor L, Morrison G. A Phase 2, Double‐Blind,
Placebo‐Controlled Trial to Investigate Potential Drug‐Drug Interactions Between
Cannabidiol and Clobazam. Journal of Clinical Pharmacology. 2020;60(10):1304-13.
34. FDA. Clinical Safety Review of randomized controlled trials Epidyolex® In: Research
CfDEa, editor. US2017. p. Cannabidiol; Ellis F. Unger, M.D. Reference ID: 4276052 (The
page number in the pdf file is 145 – 207). Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210365Orig1s000MedR.pdf
35. Therapeutic Goods Adminstration . Australian Product Information – Epidyolex®
(Cannabidiol) Oral Solution. 2021.
36. Lile JA, StilKelly TH, Hays LR. Separate and combined effects of the GABA(B) agonist
baclofen and DELTA9-THC in humans discriminating DELTA9-THC. Drug & Alcohol
Dependence. 2012;126(1-2):216-23.
37. Singh RK, Sti;Dillon B, Tatum DA, Van Poppel KC, Bonthius DJ. Drug-Drug Interactions
Between Cannabidiol and Lithium. Child Neurology Open. 2020;7(no pagination).
38. Wilens TE,Biederman J, Spencer TJ. Case study: adverse effects of smoking marijuana
while receiving tricyclic antidepressants. Journal of the American Academy of Child &
Adolescent Psychiatry. 1997;36(1):45-8.
39. Hillard JR, Vieweg WV. Marked sinus tachycardia resulting from the synergistic effects of
marijuana and nortriptyline. American Journal of Psychiatry. 1983;140(5):626-7.
40. Mannion V. Case report: Adverse effects of taking tricyclic antidepressants and smoking
marijuana. Canadian Family Physician. 1999;45(NOV.):2683-4.
41. Kanakis Jr C, Pouget JM, Rosen K. The effects of delta-9-tetrahydrocannabinol
(cannabis) on cardiac performance with and without beta blockade. Circulation.
1976;53(4):703-7.
42. Anderson LL, Doohan PT, Oldfield L, Kevin RC, Arnold JC, Berger M, et al. Citalopram
and Cannabidiol: In Vitro and In Vivo Evidence of Pharmacokinetic Interactions Relevant
to the Treatment of Anxiety Disorders in Young People. Journal of clinical
psychopharmacology. 2021;41(5):525-33.
43. Anderson LL, Arnold JC, McGregor IS, Nation TR. A Potential Drug-Gene-Drug
Interaction Between Cannabidiol, CYP2D6*4, and Fluoxetine: A Case Report. Journal of
Clinical Psychopharmacology. 2022;42(4):422-4.
44. Ganesh S, Cortes-Briones J, Ranganathan M, Radhakrishnan R, Skosnik PD, D’Souza
DC. Psychosis-relevant effects of intravenous delta-9-tetrahydrocannabinol: a mega
analysis of individual participant-data from human laboratory studies. International Journal
of Neuropsychopharmacology. 2020;23(9):559-70.
45. Gupta SS, De Aquino JP, D'Souza DC, Ranganathan M. Effects of haloperidol on the
delta-9-tetrahydrocannabinol response in humans: a responder analysis.
Psychopharmacology. 2019;236(9):2635-40.
46. Kleinloog DSt, Liem-Moolenaar M, Jacobs G, Klaassen E, de Kam M, Hijman R, et al.
Does olanzapine inhibit the psychomimetic effects of DELTA9-tetrahydrocannabinol?
Journal of Psychopharmacology. 2012;26(10):1307-16.
47. Forney R, 4Martz R, Lemberger L. The combined effect of marihuana and
dextroamphetamine. Annals of the New York Academy of Sciences. 1976;Vol.281:162-
70.
48. Kollins SH, Schoenfelder EN, English JS, Holdaway A, Van Voorhees E, O'Brien BR, et
al. An exploratory study of the combined effects of orally administered methylphenidate
and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects,
and performance in healthy adults. Journal of Substance Abuse Treatment.
2015;48(1):96-103.
49. Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid-opioid interaction
in chronic pain. Clinical Pharmacology and Therapeutics. 2011;90(6):844-51.
50. Roberts JD, Gennings C, Shih M. Synergistic affective analgesic interaction between
delta-9- tetrahydrocannabinol and morphine. European Journal of Pharmacology.
2006;530(1-2):54-8.
51. Bindler RJ, Watson CJW, Lyons AJ, Skeiky L, Lewis J, McDonell M, et al. Drug-Drug
Interaction Between Orally Administered Hydrocodone-Acetaminophen and Inhalation of
Cannabis Smoke: A Case Report. Hospital Pharmacy. 2022;57(4):518-25.
52. Cooper ZD, Bedi G, Ramesh D, Balter R, Comer SD, Haney M. Impact of co-
administration of oxycodone and smoked cannabis on analgesia and abuse liability.
Neuropsychopharmacology. 2018;43(10):2046-55.
53. Madden K, Tanco K, Bruera E. Clinically significant drug-drug interaction between
methadone and cannabidiol. Pediatrics. 2020;145(6) (no pagination)(e20193256).
54. Vierke C, Marxen B, Boettcher M, Hiemke C, Havemann-Reinecke U. Buprenorphine-
cannabis interaction in patients undergoing opioid maintenance therapy. European
Archives of Psychiatry and Clinical Neuroscience. 2021;271(5):847-56.
55. Klotz KA, Hirsch M, Heers M, Schulze-Bonhage A, Jacobs J. Effects of cannabidiol on
brivaracetam plasma levels. Epilepsia. 2019;60(7):e74-e7.
56. Ridout KK,Young-Wolff KC, Ridout SJ. A Change in Blood Carbamazepine Levels
Associated With Cannabis Use: Implications for Clinical Practice. Journal of Clinical
Psychiatry. 2021;82(3):11.
57. VanLandingham KE, Crockett J, Taylor L, Morrison G. A Phase 2, Double-Blind, Placebo-
Controlled Trial to Investigate Potential Drug-Drug Interactions Between Cannabidiol and
Clobazam. Journal of Clinical Pharmacology. 2020;60(10):1304-13.
58. Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP. Interactions between cannabidiol
and commonly used antiepileptic drugs. Epilepsia. 2017;58(9):1586-92.
59. Morrison G, Szaflarski J, Patsalos P, Gidal B, VanLandingham K, Critchley D. Drug-drug
interaction studies (DDIS) with coadministration of cannabidiol (CBD) and Clobazam
(CLB), Valproate (VPA), Stiripentol (STP), or Midazolam (MDZ) in healthy volunteers
(HVTS) and adults with epilepsy. Epilepsia. 2019;60(Supplement 2):71.
60. Potey C, Bodeau S, Bacquet M, Gaulier JM, Trauffler A, Gras-Champel V, et al. Drug
interaction between cannabidiol and clobazam: Case(s) for concern? Fundamental and
Clinical Pharmacology. 2022;36(Supplement 1):138.
61. Evans MA, Martz R, Rodda BE, Lemberger L, Forney RB. Effects of marihuana
dextroamphetamine combination. Clinical Pharmacology and Therapeutics.
1976;20(3):350-8.
62. Roberts JD, Gennings C, Shih M. Synergistic affective analgesic interaction between
delta-9-tetrahydrocannabinol and morphine. European Journal of Pharmacology.
2006;530(1-2):54-8.
63. Cooper ZD, Haney M. Opioid antagonism enhances marijuana's effects in heavy
marijuana smokers. Psychopharmacology. 2010;211(2):141-8.
64. Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid-opioid interaction
in chronic pain. Clinical Pharmacology & Therapeutics. 2011;90(6):844-51.
65. Zendulka O, Dovrtelova G, Noskova K, Turjap M, Sulcova A, Hanus L, et al.
Cannabinoids and cytochrome P450 interactions. Current Drug Metabolism.
2016;17(3):206-26.
66. Medicinal cannabis: what would you like to know. NPS Medicinewise, 2020. Available
from: https://www.nps.org.au/assets/Medicinal-cannabis-FAQs-new.pdf

Authors

Dr Joanna Harnett (she/her) BHSc, MHSc, PhD is a senior lecturer at the University of Sydney School of Pharmacy engaged in complementary medicines research and education.

Jocelin Chan (she/her) BPharm, PhD candidate, University of Sydney School of Pharmacy is a registered pharmacist and a Sydney pharmacy owner. 

Dr Jennifer Hunter (she/her) BMed, MScPH, PhD, FASLM is a general practitioner, Director of Health Research Group, and sits on the TGA Advisory Committee on Complementary Medicines.

Acknowledgements 

Joel Siciliano, Haohan Qi Master of Pharmacy students, University of Sydney, for their contribution.

Professor Andrew McLachlan (he/him) BPharm, PhD, FPS, FACP, MCPA, MSHPA, Dean of Pharmacy, University of Sydney, critically reviewed this article.